For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative (n = 32). Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive (n = 21). Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aβ+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. AD biomarker positivity was determined using a published CSF p-tau/Aβ ratio cut-score. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived a priori CBF regions of interest (ROIs) were examined. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Fifty-three non-demented Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. However, there is little known about the association between change in IIV and CBF over time. We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aβ) positive. Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer’s disease (AD).
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